The Link Between Methylation, Cholesterol, and Heart Disease (PEMT)

PEMT (Phosphatidylethanolamine N-methyltransferase) encodes an enzyme that makes phosphatidylcholine (PC) through a methylation reaction [R, R, R].

PEMT makes sure you get enough choline in the absence of food sources. It’s mainly expressed in the liver and accounts for 30% of liver PC production. Choline and PC are essential for [R, R, R]:

• Fat transport and metabolism
• Heart and brain health
• Cell membranes and cellular communication 

PEMT produces phosphatidylcholine (PC) in the liver via methylation. It supplies choline and PC in the absence of food sources, thus maintaining fat metabolism, heart and brain health, and cell structure.

Homocysteine Levels

In a study of Mexican women, the ‘T’ allele of one PEMT variant, rs7946, was associated with high homocysteine levels during folate deficiency. The effect was significant only in women with the homozygous ‘TT’ genotype [R].

Another PEMT variant, rs12325817, had a similar effect on healthy pregnant women. Carriers of the ‘G’ allele who didn’t get enough dietary folate or choline had 20% or 25% higher homocysteine levels, respectively [R].

Why High Homocysteine is Bad

Elevated homocysteine (hyperhomocysteinemia) is a significant risk factor for heart disease. It also correlates with:

• Alzheimer’s disease and dementia  [R, R]
• Diabetes and insulin resistance [R, R] 
• Depression [R, R] 
• Autoimmune diseases [R, R, R] 

These variants have a bigger impact on women because estrogen is the main stimulator of PEMT activity. Therefore, ladies should keep an especially close eye on this gene [R].

Two PEMT variants (rs7946-T and rs12325817-G) correlate with high homocysteine levels in cases of poor folate and choline intake. High homocysteine is associated with heart disease, Alzheimer’s, diabetes, and depression.

Cholesterol Levels

In two trials with almost 500 participants, those with the ‘T’ allele at rs7946 had significantly lower levels of HDL cholesterol [R, R].

HDL or the "good cholesterol" removes fat deposits from your blood vessels and shields your heart. According to the famous Framingham study, an increase in HDL of 10 mg/L can drop the risk of heart disease by 2-3% [R, R, R].

To make things worse, carriers of this variant also had higher LDL (the “bad cholesterol”) in one of the above trials [R].

Studies observed these effects in people with obesity and fatty liver, so pay special attention to your PEMT variants if you have a metabolic disorder.

Carriers of the ‘T’ allele at rs7946 have significantly lower HDL levels and may, therefore, be vulnerable to heart disease. People with metabolic disorders are more prone to the negative effects of this variant.

Other Significant Variants

Two comprehensive studies (over 85,000 participants each) have found different genetic variations associated with stroke and heart disease. Two of them, rs12936587-G and rs12449964-C, belong to the PEMT gene [R, R].

The ‘G’ allele at rs12936587 is associated with 7% higher rates of heart disease and 16% higher rates of stroke [R].

Among its other crucial roles in your body, methylation is responsible for converting homocysteine to methionine. Two different pathways enable this: one using folate and vitamin B12, and another using betaine (see the image above) [R].

When folate or vitamin B12 are restricted, your body focuses on the betaine pathway, which requires a steady supply of choline and betaine from food sources and PEMT activity.

The above PEMT variants, rs12325817 and rs7946, reduce enzyme activity and impair choline production. Thus, PEMT can’t compensate for low folate and choline intake. If you have reduced PEMT activity, it’s essential to get enough of these nutrients [R, R, R].

The body has another option for removing homocysteine: conversion to cysteine via the transsulfuration pathway (see image). This pathway depends on vitamin B6.

You need adequate folate and choline supplies to metabolize homocysteine. Specific PEMT variants may impair choline production, and that's when folate and choline deficiencies come to the fore.

Why Lower PEMT Can Be Beneficial

At the same time, PEMT activity raises homocysteine levels. For each molecule of phosphatidylcholine produced, PEMT releases three molecules of homocysteine [R].

In the above study on pregnant women, those with the ‘CC’ genotype at rs12325817 (more active PEMT) had higher homocysteine levels when choline and folate intakes were adequate [R].

It’s also interesting that the ‘T’ allele on rs7946 (which lowers PEMT activity) is much more common than the ‘C’ allele among European descendants. As the choline intake of European ancestors increased, their bodies may have adapted by lowering PEMT activity and sparing methyl groups for other vital reactions [R, R, R].

When your intake of choline and folate is sufficient, lower PEMT activity may prevent excessive homocysteine production and spare valuable methyl groups.

SNP Summary and Table

Primary SNPs: 

PEMT rs7946

• ‘C’ = Doesn't impact heart health
• ‘T’ = Linked to worse heart health

Population Frequency:

• 50% of European descendants have the (TT) genotype
• 4% of East-Asian descendants (China, Japan) have this genotype

PEMT rs12325817

• ‘C’ = Doesn't impact heart health
• ‘G’ = Linked to worse heart health

Population Frequency:

• Around 23% of people from Europe have the GG genotype
• This genotype is almost non-existent among African and Asian descendants

Other important SNPs:

PEMT rs12936587

• ‘A’ = Linked to better heart health
• ‘G’ = Linked to worse heart health

PEMT rs12449964

• ‘T’ = Linked to better heart health
• ‘C’ = Linked to worse heart health

The last two SNPs are almost always inherited together:

• Around 57% of the general population has the 'problematic' genotypes: GG and CC
• Around 31% of European descendants have these genotypes